-
Integrative and Comparative Biology Jul 2019Contemporary papers and book chapters on nephrology open with the assumption that human kidney development passes through three morphological stages: pronephros,... (Review)
Review
Contemporary papers and book chapters on nephrology open with the assumption that human kidney development passes through three morphological stages: pronephros, mesonephros, and metanephros. Current knowledge of the human pronephros, however, appears to be based on only a hand full of human specimens. The ongoing use of variations in the definition of a pronephros hampers the interpretation of study results. Because of the increased interest in the anamniote pronephros as a genetic model for kidney organogenesis we aimed to provide an overview of the literature concerning kidney development and to clarify the existence of a pronephros in human embryos. We performed an extensive literature survey regarding vertebrate renal morphology and we investigated histological sections of human embryos between 2 and 8 weeks of development. To facilitate better understanding of the literature about kidney development, a referenced glossary with short definitions was composed. The most striking difference between pronephros versus meso- and metanephros is found in nephron architecture. The pronephros consists exclusively of non-integrated nephrons with external glomeruli, whereas meso- and metanephros are composed of integrated nephrons with internal glomeruli. Animals whose embryos have comparatively little yolk at their disposal and hence have a free-swimming larval stage do develop a pronephros that is dedicated to survival in aquatic environments. Species in which embryos do not have a free-swimming larval stage have embryos that are supplied with a large amount of yolk or that develop within the body of the parent. In those species the pronephros is usually absent, incompletely developed, and apparently functionless. Non-integrated nephrons were not identified in histological sections of human embryos. Therefore, we conclude that a true pronephros is not detectable in human embryos although the most cranial part of the amniote excretory organ is often confusingly referred to as pronephros. The term pronephros should be avoided in amniotes unless all elements for a functional pronephros are undeniably present.
Topics: Animals; Humans; Kidney; Pronephros; Vertebrates
PubMed: 30649320
DOI: 10.1093/icb/icz001 -
Results and Problems in Cell... 2017The pronephros is the first kidney type to form in vertebrate embryos. The first step of pronephrogenesis in the zebrafish is the formation of the intermediate mesoderm... (Review)
Review
The pronephros is the first kidney type to form in vertebrate embryos. The first step of pronephrogenesis in the zebrafish is the formation of the intermediate mesoderm during gastrulation, which occurs in response to secreted morphogens such as BMPs and Nodals. Patterning of the intermediate mesoderm into proximal and distal cell fates is induced by retinoic acid signaling with downstream transcription factors including wt1a, pax2a, pax8, hnf1b, sim1a, mecom, and irx3b. In the anterior intermediate mesoderm, progenitors of the glomerular blood filter migrate and fuse at the midline and recruit a blood supply. More posteriorly localized tubule progenitors undergo epithelialization and fuse with the cloaca. The Notch signaling pathway regulates the formation of multi-ciliated cells in the tubules and these cells help propel the filtrate to the cloaca. The lumenal sheer stress caused by flow down the tubule activates anterior collective migration of the proximal tubules and induces stretching and proliferation of the more distal segments. Ultimately these processes create a simple two-nephron kidney that is capable of reabsorbing and secreting solutes and expelling excess water-processes that are critical to the homeostasis of the body fluids. The zebrafish pronephric kidney provides a simple, yet powerful, model system to better understand the conserved molecular and cellular progresses that drive nephron formation, structure, and function.
Topics: Animals; Models, Animal; Organogenesis; Pronephros; Zebrafish; Zebrafish Proteins
PubMed: 28409341
DOI: 10.1007/978-3-319-51436-9_2 -
Methods in Cell Biology 2016The kidney of the zebrafish shares many features with other vertebrate kidneys including the human kidney. Similar cell types and shared developmental and patterning...
The kidney of the zebrafish shares many features with other vertebrate kidneys including the human kidney. Similar cell types and shared developmental and patterning mechanisms make the zebrafish pronephros a valuable model for kidney organogenesis. Here we review recent advances in studies of zebrafish pronephric development and provide experimental protocols to analyze kidney cell types and structures, measure nephron function, live image kidney cells in vivo, and probe mechanisms of kidney regeneration after injury.
Topics: Animals; Gene Expression Regulation, Developmental; Humans; Kidney; Nephrons; Organogenesis; Pronephros; Regeneration; Zebrafish
PubMed: 27312500
DOI: 10.1016/bs.mcb.2016.03.041 -
Clinical Science (London, England :... Dec 2018The renin-angiotensin system (RAS) is highly conserved, and components of the RAS are present in all vertebrates to some degree. Although the RAS has been studied since... (Review)
Review
The renin-angiotensin system (RAS) is highly conserved, and components of the RAS are present in all vertebrates to some degree. Although the RAS has been studied since the discovery of renin, its biological role continues to broaden with the identification and characterization of new peptides. The evolutionarily distant zebrafish is a remarkable model for studying the kidney due to its genetic tractability and accessibility for imaging. The zebrafish pronephros is an especially useful kidney model due to its structural simplicity yet complex functionality, including capacity for glomerular and tubular filtration. Both the pronephros and mesonephros contain renin-expressing perivascular cells, which respond to RAS inhibition, making the zebrafish an excellent model for studying the RAS. This review summarizes the physiological and genetic tools currently available for studying the zebrafish kidney with regards to functionality of the RAS, using novel imaging techniques such as SPIM microscopy coupled with targeted single cell ablation and synthesis of vasoactive RAS peptides.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Gene Expression Regulation, Developmental; Kidney Diseases; Luminescent Proteins; Pronephros; Renin-Angiotensin System; Signal Transduction; Zebrafish; Zebrafish Proteins
PubMed: 30518571
DOI: 10.1042/CS20180721 -
Journal of the American Society of... Mar 2021Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic...
BACKGROUND
Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease.
METHODS
Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. and studies determined the functional significance of the mutations identified.
RESULTS
Three biallelic variants of the transcriptional regulator were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in embryos disrupted pronephric development. Human wild-type RNA rescued the disruption, but the three variants did not. Finally, CRISPR-mediated knockout of in human podocytes led to dysregulation of several renal developmental genes.
CONCLUSIONS
Variants in can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.
Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Cell Line; Child, Preschool; DNA-Binding Proteins; Female; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Gene Knockout Techniques; Hernia, Hiatal; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Male; Microcephaly; Models, Molecular; Mutation, Missense; Nephrosis; Nephrotic Syndrome; Podocytes; Polymorphism, Single Nucleotide; Pronephros; Protein Stability; Transcription Factors; Xenopus laevis; Zinc Fingers
PubMed: 33593823
DOI: 10.1681/ASN.2020040490 -
Pediatric Nephrology (Berlin, Germany) Feb 2017The nephron is the functional subunit of the vertebrate kidney and plays important osmoregulatory and excretory roles during embryonic development and in adulthood.... (Review)
Review
The nephron is the functional subunit of the vertebrate kidney and plays important osmoregulatory and excretory roles during embryonic development and in adulthood. Despite its central role in kidney function, surprisingly little is known about the molecular and cellular processes that control nephrogenesis. The zebrafish pronephric kidney, comprising two nephrons, provides a visually accessible and genetically tractable model system for a better understanding of nephron formation. Using this system, various developmental processes, including the commitment of mesoderm to a kidney fate, renal tubule proliferation, and migration, can be studied during nephrogenesis. Here, we discuss some of these processes in zebrafish with a focus on the pathways that influence renal tubule cell morphogenesis.
Topics: Animals; Kidney Tubules; Morphogenesis; Organogenesis; Zebrafish
PubMed: 26942753
DOI: 10.1007/s00467-016-3353-1 -
Cells Apr 2022The anterior-posterior (AP) axis in chordates is regulated by a conserved set of genes and signaling pathways, including genes and retinoic acid (RA), which play...
The anterior-posterior (AP) axis in chordates is regulated by a conserved set of genes and signaling pathways, including genes and retinoic acid (RA), which play well-characterized roles in the organization of the chordate body plan. The intermediate mesoderm (IM), which gives rise to all vertebrate kidneys, is an example of a tissue that differentiates sequentially along this axis. Yet, the conservation of the spatiotemporal regulation of the IM across vertebrates remains poorly understood. In this study, we used a comparative developmental approach focusing on non-conventional model organisms, a chondrichthyan (catshark), a cyclostome (lamprey), and a cephalochordate (amphioxus), to assess the involvement of RA in the regulation of chordate and vertebrate pronephros formation. We report that the anterior expression boundary of early pronephric markers ( and ), positioned at the level of somite 6 in amniotes, is conserved in the catshark and the lamprey. Furthermore, RA, driving the expression of genes like in amniotes, regulates the anterior pronephros boundary in the catshark. We find no evidence for the involvement of this regulatory hierarchy in the AP positioning of the lamprey pronephros and the amphioxus pronephros homolog, Hatschek's nephridium. This suggests that despite the conservation of and expressions in chordate pronephros homologs, the responsiveness of the IM, and hence of pronephric genes, to RA- and -dependent regulation is a gnathostome novelty.
Topics: Animals; Chordata; Genes, Homeobox; Lampreys; Pronephros; Tretinoin; Vertebrates
PubMed: 35455988
DOI: 10.3390/cells11081304 -
Biochemical and Biophysical Research... Jan 2018Eph/ephrin molecules are widely expressed during embryonic development, and function in a variety of developmental processes. Here we studied the roles of the Eph...
Eph/ephrin molecules are widely expressed during embryonic development, and function in a variety of developmental processes. Here we studied the roles of the Eph receptor EphA7 and its soluble form in Xenopus pronephros development. EphA7 is specifically expressed in pronephric tubules at tadpole stages and knockdown of EphA7 by a translation blocking morpholino led to defects in tubule cell differentiation and morphogenesis. A soluble form of EphA7 (sEphA7) was also identified. Interestingly, the membrane level of claudin6 (CLDN6), a tetraspan transmembrane tight junction protein, was dramatically reduced in the translation blocking morpholino injected embryos, but not when a splicing morpholino was used, which blocks only the full length EphA7. In cultured cells, EphA7 binds and phosphorylates CLDN6, and reduces its distribution at the cell surface. Our work suggests a role of EphA7 in the regulation of cell adhesion during pronephros development, whereas sEphA7 works as an antagonist.
Topics: Animals; Cell Membrane; Claudins; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Oligodeoxyribonucleotides, Antisense; Pronephros; Receptor, EphA7; Solubility; Xenopus Proteins; Xenopus laevis
PubMed: 29223398
DOI: 10.1016/j.bbrc.2017.12.027 -
Scientific Reports Oct 2023The nephron, functional unit of the vertebrate kidney, is specialized in metabolic wastes excretion and body fluids osmoregulation. Given the high evolutionary...
The nephron, functional unit of the vertebrate kidney, is specialized in metabolic wastes excretion and body fluids osmoregulation. Given the high evolutionary conservation of gene expression and segmentation patterning between mammalian and amphibian nephrons, the Xenopus laevis pronephric kidney offers a simplified model for studying nephrogenesis. The Lhx1 transcription factor plays several roles during embryogenesis, regulating target genes expression by forming multiprotein complexes with LIM binding protein 1 (Ldb1). However, few Lhx1-Ldb1 cofactors have been identified for kidney organogenesis. By tandem- affinity purification from kidney-induced Xenopus animal caps, we identified single-stranded DNA binding protein 2 (Ssbp2) interacts with the Ldb1-Lhx1 complex. Ssbp2 is expressed in the Xenopus pronephros, and knockdown prevents normal morphogenesis and differentiation of the glomus and the convoluted renal tubules. We demonstrate a role for a member of the Ssbp family in kidney organogenesis and provide evidence of a fundamental function for the Ldb1-Lhx1-Ssbp transcriptional complexes in embryonic development.
Topics: Animals; Xenopus laevis; LIM-Homeodomain Proteins; Gene Expression Regulation, Developmental; Transcription Factors; Kidney; Embryonic Development; Morphogenesis; Pronephros; Xenopus Proteins; Mammals
PubMed: 37794075
DOI: 10.1038/s41598-023-43662-1 -
Cells Sep 2018The structural and functional similarity of the larval zebrafish pronephros to the human nephron, together with the recent development of easier and more precise... (Review)
Review
The structural and functional similarity of the larval zebrafish pronephros to the human nephron, together with the recent development of easier and more precise techniques to manipulate the zebrafish genome have motivated many researchers to model human renal diseases in the zebrafish. Over the last few years, great advances have been made, not only in the modeling techniques of genetic diseases in the zebrafish, but also in how to validate and exploit these models, crossing the bridge towards more informative explanations of disease pathophysiology and better designed therapeutic interventions in a cost-effective in vivo system. Here, we review the significant progress in these areas giving special attention to the renal phenotype evaluation techniques. We further discuss the future applications of such models, particularly their role in revealing new genetic diseases of the kidney and their potential use in personalized medicine.
PubMed: 30200518
DOI: 10.3390/cells7090130